Heart valve replacement therapy is in the midst of a major paradigm shift. Improvements in imaging, catheter technology and stent design have made transcatheter replacement of the aortic and pulmonic valves clinical realities. A transcatheter approach to mitral valve replacement (TMVR) would represent a major advance in treatment since approximately 2.4 million Americans suffer from moderate to severe ischemic mitral regurgitation (IMR) with the vast majority being deemed too sick or debilitated to tolerate open-heart surgery. Successful TMVR requires: 1) a sutureless anchoring mechanism~ 2) a perivalvular sealing strategy and 3) foldability. As the result of extensive preliminary work we have developed a novel anchoring and sealing mechanism for TMVR. The current prototype is a self-expanding valved stent constructed from a polytetrafluoroethylene covered nitinol wire frame. Anchoring is facilitated by arms emanating from the ventricular end of the device which are designed to atraumatically insinuate themselves around chordae and leaflets. Our sealing mechanism relies on the flexibility of the stent design which allows the device to be slightly oversized thereby permitting the device to conform snuggly to the annulus and leaflet cone. In preliminary work we have demonstrated that our TMVR concept can anchor and seal robustly in large animal models. The goal of the proposed project is to optimize the design of the current prototype to maximize device foldability and delivery without compromising valve fixation and seal. The development process will follow a graded approach. Specific Aim 1 is to further develop the anchoring and sealing technology using open surgical techniques to evaluate design iterations. The result of this development stage will be a sutureless mitral valve replacement. Specific Aim 2A will be to develop a minimally invasive surgical delivery system which will ultimately facilitate off pump mitral valve replacement via a small right thoracotomy in humans. Specific Aim 2B is to further enhance the delivery system to allow mitral valve replacement via peripheral vein and transatrial septal approach.